Variation of HERV-K content and expression in humans: Evolution, cancer, and irradiation

Abstract

Ionizing Radiation (IR) has been shown to increase the immunogenicity of cancer cells in vitro and in vivo. IR has been reported to increase the transcriptional activity of many viruses in infected cells. We hypothesized that IR could reactivate or increase transcription of Human Endogenous Retrovirus K (HERV-K), the most recent retrovirus that infected the human germline, and thus the most intact among all the HERVs, and that encoded HERV-K-derived peptides could increase the diversity of the antigen repertoire presented by irradiated cancer cells thereby contributing to the increased immunogenicity following IR. HERV-Ks are known to be transcribed in numerous diseases including cancer.;In this thesis, I present studies initiated to detect HERV-K DNA proviruses in genomic sequencing data or to better characterize RNA transcripts in cancer cells, with the goal of a more comprehensive understanding of virus/host relationship and their future exploitation for novel anti-cancer therapies.;A dedicated bioinformatic pipeline was developed to identify new HERV-K insertions in short reads databases obtained by massive parallel sequencing. This was first tested on genome sequence reads from Neanderthal and Denisovan archaic hominins. This analysis yielded a partially shared set of HERV-K specific to these hominins but absent in modern Homo sapiens, thus confirming a previously proposed phylogeny in which the human lineage diverged from the others before they diverged from each other.;To test the effect of IR on HERV-K transcription, cancer cell lines from cancer sites commonly treated with radiotherapy were analyzed by RT-PCR and qRT-PCR at specific times after varying doses of gamma-irradiation. HERV-K transcription was identified in almost all the cell lines studied including spliced transcripts for Rec and Env viral proteins. Unexpectedly, a large fraction of HERV-K transcripts were spliced at previously undescribed alternative sites. Specific, active HERV-K loci were identified from polymorphic nucleotides. IR increased the levels of HERV-K transcripts from two- to eight-fold in prostate cancers. These results warrant further investigation of HERV-K as a potential target for radiation-enhanced immunotherapy, particularly of prostate cancer.